The Crithidia luciliae immunofluorescence (CLIF) assay is widely used to detect antibodies to native dsDNA in the diagnosis and management of systemic lupus erythematosus (SLE). However, sera from patients with SLE, rheumatoid arthritis, systemic sclerosis, drug-induced lupus erythematosus, and Sjogren's syndrome have given false-positive CLIF results. The frequency was 5% for SLE, 16% for drug-induced LE, and 5% for rheumatoid arthritis. Such false positivity was effectively eliminated by pretreatment of Crithidia luciliae smears with 0.1 N HCl. Hydrochloric acid pretreatment of Crithidia luciliae smears renders the CLIF test more specific for the detection of anti-dsDNA antibodies, without sacrificing its sensitivity and specificity. In the future, modification of routine Crithidia luciliae immunofluorescence with 0.1 N HCl pretreatment is recommended.